The long-term goal of this proposal is to evaluate the preclinical translational potential of anti-diabetic drug, metformin, in the relapsing/remitting (RR) model and chronic animal models of multiple sclerosis (MS). The present proposal is based on the two novel recently published key findings: 1. AMP-activated protein kinase (AMPK), an energy sensing metabolic switch, is down regulated in immune cells during EAE disease. 2. Metformin, an activator of AMPK and well known drug for metabolic disorder, provided prophylactic efficacy in RR (SJL/J) and chronic (C57B6) mouse models of MS due to its anti-inflammatory properties. For translational potential for any drug, it is important to examine its efficacy in relevant animal model(s) when they exhibit clinical symptoms. In the present study we propose to examine the therapeutic potential of metformin in RR and chronic models in EAE disease as a pre-clinical study. We propose aim: 1) To examine the therapeutic effect of metformin in the disease process of RR and chronic models of EAE. To examine metformin as a drug for MS patients, it is important that metformin has to show its effectiveness when given at disease onset. Therefore, in this study we have planned detailed study to examine the therapeutic effect of metformin in RR and chronic mouse models of MS when animals show clinical sign of disease. 2) Validation of therapeutic protection of metformin by pathological and biochemical analysis of CNS tissues of metformin- and vehicle treated EAE. Under this aim, we propose to examine the pathology (status of inflammation, infiltration of mononuclear cells, demyelination and axonal loss) and metabolic derangement (activity of AMPK, lipid profile and fatty acid composition) as a parameter in CNS to evaluate the effect of therapeutic doses of metformin in both EAE models. The novelty of this study is to evaluate a possibility of using anti-diabetic drug for MS that has a direct translational implication. If successful, metformin can be a drug of choice as it has good bioavailability and is given orally which may cut down the cost of therapy, frequent doctor visits and painful administration of drugs. Our preliminary data promises great implications for clinical research and offers the possibility of developing effective therapy alone or in combination with existing therapies for MS and other neuro-inflammatory diseases. Public Health Relevance: Multiple Sclerosis (MS) is a chronic disease of the brain, which affects mostly young adults during their most productive years. There is no cure or treatment available for MS. However, number of medications can be used to treat the disease symptomatically such as corticosteroids, Interferonss-1B (Betaseron), Interferonss-1[unreadable] (Avonex) and Copolymer 1. We propose to examine here, metformin (a widely used drug for diabetes) in animal model of EAE. Our preliminary data shows some promise, that this diabetic drug may be a drug for MS too. In this work we will treat mice with metformin when they already show sign of disease, to see the relevance to MS patient therapy. Metformin has so many properties like anti-inflammatory, anti-oxidant, restore endothelial functions and activates enzyme which regulates energy in body (AMP-activated protein kinase), without many side effects. Most interestingly, it has good bioavailability, so metformin is given orally which may cut down the cost of therapy, frequent doctor visits and painful administration of drugs. If metformin shows encouraging results, it will have great implications for clinical research and may offer the possibility of developing into an effective therapy alone or in combination with current therapy for MS. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.